Campylobacter species including C. jejuni and C. coli are the most common bacterial causes of human gastroenteritis in the United States. Increasing resistance of Campylobacter to clinical antibiotics poses a significant threat to public health and raises an urgent need for alternative strategies to prevent and control Campylobacter infections. Iron acquisition is essential for survival and colonization of pathogenic bacteria in the host and thus has been targeted for iron-dependent pathogen control. In Campylobacter, the ferric enterobactin (FeEnt) acquisition system is of particular interest because of the extremely high affinity of Ent for iron, the production of Ent by a wide variety of gut commensal bacteria, and the critical role of FeEnt receptors, CfrA and CfrB, in colonization of intestinal Campylobacter. Based on our preliminary studies, we hypothesize that both the CfrA- and CfrB-dependent FeEnt acquisition systems play a critical role in the pathophysiology of Campylobacter despite considerable difference in their function, genetic components, and molecular interaction;thus, FeEnt acquisition systems in Campylobacter are promising targets for vaccine and antimicrobial development. To test these hypotheses, we plan to 1) examine functional characteristics of FeEnt receptors and determine molecular pathways of CfrA- and CfrBdependent FeEnt acquisition systems in Campylobacter;2) Characterize the FeEnt esterase Cee and the ferric/flavin reductase system in Campylobacter;and 3) evaluate the immunogenicity and protective efficacy of CfrA and CfrB subunit vaccines in a chicken model of Campylobacter infection. This project will substantially improve our understanding of the molecular pathways of two unique FeEnt acquisition systems in Campylobacter, reveal the mechanistic features of key components involved in this important pathophysiological process, and provide critical information about the feasibility of targeting FeEnt receptors for immune protection against Campylobacter colonization in humans. The novel information obtained from this project may also establish that Campylobacter is an ideal model organism to study FeEnt acquisition in bacteria.